Autonomous Treatment of Bacterial Infections in Vivo Using Antimicrobial Micro- and Nanomotors

Abstract

The increasing resistance of bacteria to existing antibiotics constitutes a major public health threat globally. Most current antibiotic treatments are hindered by poor delivery to the infection site, leading to undesired off-target effects and drug resistance development and spread. Here, we describe micro- and nanomotors that effectively and autonomously deliver antibiotic payloads to the target area. The active motion and antimicrobial activity of the silica-based robots are driven by catalysis of the enzyme urease and antimicrobial peptides, respectively. These antimicrobial motors show micromolar bactericidal activity in vitro against different Gram-positive and Gram-negative pathogenic bacterial strains and act by rapidly depolarizing their membrane. Finally, they demonstrated autonomous anti-infective efficacy in vivo in a clinically relevant abscess infection mouse model. In summary, our motors combine navigation, catalytic conversion, and bactericidal capacity to deliver antimicrobial payloads to specific infection sites. This technology represents a much-needed tool to direct therapeutics to their target to help combat drug-resistant infections.

Enzyme-powered micro- and nano-motors: key parameters for an application-oriented design

“…Enzymatic motors are widely reported to be used in the forms of mesoporous silica [69][70][71][72][73][74][75][76][77][78][79] , core-shell structures 80 or rigid silica. 78,[81][82][83][84][85][86][87] Silica allows for easy spherical formation and surface modication, as well as biocompatibility and molecule encapsulation inside mesopores making this material promising for clinical translation. 88 Hence, it is combined with polymers to additionally confer these properties, for example silica with polystyrene (PS-SiO 2 ) 89 , poly(sodium styrene sulfonate) (PSS-SiO 2 ), 57 PNIPAM (PNIPAM-SiO 2 ) 90 or other combinations of increasing complexity like silica with polydopamine, poly(L-lysine) and poly(ethylene glycol) (SiO 2 -PDA-PLL-PEG) 91 .…”

“…4C) that consumes urea (CO(NH 2 ) 2 ) and releases ammonium ions (NH 4 + ) and bicarbonate (CO 3 2À ). 14,[20][21][22]31,34,36,39,44,60,[70][71][72][73][74][78][79][80][81]83,84,86,89,90,92,93,99,[117][118][119][120]129 Interestingly, a study of urease-powered micromotors shows that the gradient of ionic products may be responsible for the self-propulsion, 84 an ionic self-diffusiophoretic mechanism that has been further supported by theoretical models. 82,136 This was proved by the decreasing speed of urease micromotors aer exposing them to different ionic compounds.…”

“…87 Beyond fundamental mechanistic aspects, this enzyme is gaining much interest to propel nanomotors for biomedical applications given its substrate bioavailability, biocompatibility, pH basication and high turnover rate. Urease-powered motors have been applied in different studies to change the media to basic pH 81,84 and ght bacteria, 46,72,78,93 and for treatments against bladder cancer, 137 where urea is bioavailable. 22,60,73,96 Due to their biocompatibility and efficient active motion, urease motors have been expanded to multiple other biomedical applications.…”

“…As observed in each of the previous sections, the different parameters and optimal design of enzymatic micro-and nanomotors are determined by the nal application for that specic motor. For the future of biomedical applications, spherical shapes created from materials with biological-like properties such as biocompatibility, biodegradability, exibility, solubility, and permeability will be promoted to offer native-like properties, which points towards bio-inspired materials like liposomes 20,21,41,57,106,116 (C) visualization inside organisms exploiting enhanced targeting and penetration, 25,40,60,70,93,100 (D) photo-and magnetic thermal treatment, 62,108 (E) cell and compound sensing, 17,42,47,56,78 (F) contaminant compound removal 13,72,110 and (G) bacteria capture or elimination. 58,63,69,75 or biodegradable polymers.…”

Genomewide Analysis and Biological Characterization of Cathelicidins with Potent Antimicrobial Activity and Low Cytotoxicity from Three Bat Species

“…An effective production system of recombinant cathelicidins using an engineered green fluorescent protein (GFP) as a tag protein was attempted for large-scale production of AMPs [ 61 ]. The conjugation of AMPs with nanoparticles has been suggested to overcome poor stability of AMPs in biological fluids and proteolytic degradation and to control pharmacokinetics [ 62 , 63 , 64 ].…”